Previcox Chewable Tablets (227 mg)

Description: Previcox® (firocoxib) is a selective COX-2 enzyme inhibiting-class, non-narcotic, non-steroidal anti-inflammatory drug. Firocoxib is a white crystalline compound described chemically as 3-(cyclopropylmethoxy)-4-(4-(methylsulfonyl)phenyl)-5,5-dimethylfuranone. The empirical formula is C17H20O5S, and the molecular weight is 336.4. The structural formula is shown below:

Indications: Previcox® (firocoxib) Chewable Tablets are indicated for the control of pain and inflammation associated with osteoarthritis and for the control of post-operative pain and inflammation associated with soft-tissue and orthopedic surgery in dogs.

Dosage and Administration: For osteoarthritis, the recommended dosage of Previcox® (firocoxib) for oral administration in dogs is 5 mg/kg body weight once daily. For post-operative pain and inflammation following soft-tissue and orthopedic surgery, the recommended dosage is 5 mg/kg body weight once daily, starting approximately 2 hours prior to surgery and for 2 additional days as needed. Previcox tablets are scored and dosage should be calculated in half tablet increments. Due to tablet size and scoring, dogs weighing less than 5.7 kg (12.5 lbs) cannot be accurately dosed. Previcox® tablets may be administered with or without food.

Contra-indications: Do not administer Previcox® or any NSAID if gastro-intestinal ulceration or bleeding is suspected. Do not administer concurrently with corticosteroids or other non-steroidal anti-inflammatory drugs. Do not administer to dehydrated animals. Dogs with hypersensitivity to firocoxib should not receive Previcox®.

Cautions: As with any other NSAID, carefully consider the potential benefits and risks of Previcox® (firocoxib) and other treatment options before deciding to use Previcox®. Use the lowest effective dose for the shortest duration consistent with individual response. Previcox® (firocoxib) is a highly selective COX-2 inhibitor. Non steroidal anti-inflammatories may, as a class, be associated with gastrointestinal and renal toxicity. A thorough history should be taken and a physical examination conducted prior to starting NSAID therapy. Hematological and biochemistry baseline data should be taken prior to the start of NSAID therapy and monitoring during treatment is recommended. Sensitivity to drug-associated adverse events varies with the individual patient. Patients at greatest risk for renal toxicity are those that are dehydrated, on concomitant diuretic therapy, or those with renal, cardiovascular, and/or hepatic dysfunction.

The safe use of Previcox® in breeding, pregnant or lactating dogs has not been evaluated.

Safety of this drug in dogs less than 10 weeks of age has not been established. Dosing in young animals should be observed closely, since long term administration of doses greater than 9.5 mg/kg was associated with signs of toxicity that could progress to severe if treatment was continued.

Previcox® is a highly protein-bound drug; concurrent administration of another highly protein-bound drug is not recommended. Concurrent administration of potentially nephrotoxic drugs should be carefully approached and monitored. NSAIDs may inhibit the prostaglandins that maintain normal homeostatic function. Such anti-prostaglandin effect may result in clinically significant disease in patients with underlying and pre-existing disease that has not been previously diagnosed. Appropriate monitoring procedures should be employed during all surgical procedures. Anesthetic drugs may affect renal perfusion; approach concomitant use of anesthetics and NSAIDs cautiously. The use of parental fluids during surgery should be considered to decrease potential renal complications when using NSAIDs perioperatively.

Prior to orthopedic surgery it is recommended that additional analgesic pre-anesthetic medication not of the non-steroidal anti-inflammatory or steroidal class also be used. If additional pain medication is needed after the daily dose of Previcox® (firocoxib), a non-NSAID class analgesic will be necessary.

Use of this product at doses above the recommended 5 mg/kg in puppies less than 7 months of age has been associated with serious adverse reactions, including death (see Animal Safety). Owners should be advised to observe for signs of potential drug toxicity (see Adverse Reactions and Animal Safety).

Warnings: Not for use in humans. Keep this and all medications out of the reach of children. Consult a physician in case of accidental ingestion by humans.

Adverse Reactions:

Osteoarthritis:

Previcox® was evaluated for safety in 3 multi-centered and 1 single-centered field studies for osteoarthritis involving 575 dogs of which 292 were treated with Previcox®. Dogs were treated with firocoxib at 5 to 10 mg/kg for 30 days. As shown in Table I below, decreased appetite (5.1%) and vomiting (4.8%) were the most commonly observed side effects. In these positive-controlled clinical studies, the incidence of reported side effects was similar or lower with Previcox® treatment as compared to the positive control group.

Table I - Reported Side Effects in Previcox®Field Studies for osteoarthritis

Clinical Sign

Incidence on firocoxib

%1on firocoxib

Incidence on Positive control article #1

%2on Positive control article #1

Incidence on Positive control article #2

%3on Positive control article #2

Any abnormal4

50

17.1

43

32.6

30

19.9

Anorexia

15

5.1

14

10.6

7

4.6

Emesis

14

4.8

9

6.8

11

7.3

Diarrhea

9

3.1

9

6.8

13

8.6

Pain (lack of effect)

6

2.1

5

3.8

2

1.3

Polydipsia

5

1.7

8

6.1

1

0.7

Constipation

3

1.0

1

0.8

2

1.3

Death

3

1.0

3

2.3

0

0.0

Lethargy

3

1.0

5

3.8

4

2.6

Anxiety

2

0.7

3

2.3

0

0.0

Melena

1

0.3

1

0.8

5

3.3

Otitis

1

0.3

2

1.5

0

0.0

Adypsia

0

0.0

2

1.5

0

0.0

Gastroenteritis

0

0.0

1

0.8

2

1.3

Muscle tremor

0

0.0

3

2.3

0

0.0

1Of 292 dogs treated with firocoxib

2Of 132 dogs treated with Positive control article #1

3Of 151 dogs treated with Positive control article #2

4Any abnormal refers to number of dogs that had at least one abnormal event reported during the studies.

In controlled field studies evaluating soft-tissue postoperative pain and inflammation, 258 dogs (ages 10.5 weeks to 16 years) were evaluated for safety when given Previcox® (firocoxib) at a dose of 5 mg/kg orally approximately 2 hours prior to surgery and once daily thereafter for up to 2 days. The adverse reactions presented in Table II below were observed. Dogs may have experienced more than one of the observed reactions during the study.

Post-operative pain and inflammation associated with orthopedic surgery: In controlled field studies evaluating post-operative pain and inflammation following orthopedic surgery, 226 dogs (ages 8 months to 17 years) were evaluated for safety when given Previcox® (firocoxib) at a dose of 5 mg/kg orally approximately 2 hours prior to surgery and once daily thereafter for up to 2 days. The adverse reactions presented in Table III below were observed. Dogs may have experienced more than one of the observed reactions during the study.

The following adverse reactions are based on voluntary post-approval reporting and are consistent with those reported for other cyclooxygenase inhibitory NSAID class drugs. The categories are listed in decreasing frequency by body system.

In rare situations death has been reported as an outcome of the adverse events listed above.

Clinical Pharmacology: Previcox® (firocoxib) is a cyclooxygenase-inhibiting (coxib) class, non-narcotic, non-steroidal anti-inflammatory drug (NSAID) with anti-inflammatory and analgesic activity in animal models. Firocoxib is a highly selective inhibitor of prostaglandin biosynthesis through inhibition of the inducible cyclooxygenase 2 isoenzyme (COX-2), which is responsible for various physiological processes, one of which is the synthesis of inflammatory mediators. Results from in vitro studies showed firocoxib to be highly selective for the COX-2 enzyme when canine blood was used. The clinical relevance of this in vitro data is unknown.

The pharmacokinetics of Previcox® (firocoxib) are summarized in Table IV:

Table IV - Pharmacokinetics of Firocoxib - Obtained following one administration to four male and four female beagle dogs

Parameter

Value

AUC(0-LOQ)

5 µg/hr/mL

Cmax

0.5 µg/mL

Tmax

1.25 hrs.

Terminal half life, t1/2

7.6 hrs.

Protein binding

≈ 96%

Oral bioavailability

38%

Clearance

≈ 0.4 L/hr/kg

Firocoxib is metabolized primarily in the liver and excreted primarily through bile and feces. Average steady state concentration is achieved at approximately three days.

Pharmacokinetic parameters were assessed in fed and in fasted dogs. Although the AUC and Cmax were not significantly different between the 2 groups, the time to Tmax was. Food increased the time to Cmax from 1.25 hours to 5 hours.

Field studies to determine effectiveness:

Osteoarthritis:

Previcox® Chewable Tablets were evaluated in positive-controlled, multi-center field studies involving client-owned animals to determine effectiveness of Previcox® in the control of pain and inflammation associated with osteoarthritis in dogs.

In a U.S. multi-centered, positive-controlled, non-inferiority trial, conducted at 6 veterinary clinics, which included a total of 249 dogs of various breeds, ranging in age from 11 months to 20 years and weighing 3 to 80 kilograms, 128 dogs (51.4%) were treated with Previcox® (firocoxib) at 5 to 10 mg/kg once daily for 30 days. Dogs were diagnosed with a variety of osteoarthritic conditions, including cases of hip and elbow dysplasia and degenerative joint disease. Dogs were assessed for lameness, pain on manipulation, range of motion, and joint swelling. Dogs treated with Previcox® showed a level of improvement in veterinarian assessed lameness, pain on palpation, range of motion and owner assessed improvement that was comparable to the active control. In a separate assessment, 87% of owners also rated their dogs as improved following treatment with Previcox®. In one of the studies, 89 dogs were also evaluated by force plate gait analysis. Dogs treated with Previcox® demonstrated similar improvements in limb weight bearing as compared to the positive control group.

Two additional positive-controlled, non-inferiority multi-centered trials conducted respectively in Europe and Australia, as well as a positive-controlled, non-inferiority single-centered trial in Canada, were performed at a total of 16 veterinary clinics, with 326 dogs of various breeds, ranging in age from 7 months to 19 years and weighing 3 to 86 kilograms. 164 of these dogs (50.3%) received Previcox® at 5 to 10 mg/kg once daily for 30 days. Results in these three studies were similar to those observed in the U.S. studies, with approximately 90% of dogs treated with Previcox® judged improved by the veterinarians and approximately 95% judged improved by the owners.

Overall, across the four field studies, the results for firocoxib show that approximately 89% of the dogs improved as assessed by veterinarians and 91% of the dogs improved as assessed by owners.

Previcox® Chewable Tablets were evaluated in a negative-controlled, double-blinded, multi-center field study conducted in the United States, France, Germany and Italy, and involving client-owned animals to determine effectiveness of Previcox® in the control of post-operative pain and inflammation associated with soft-tissue surgery.

258 client-owned dogs of various breeds ranging in age from 10.5 weeks to 16 years and weighing from 3.2 to 76.2 kg were randomly administered Previcox® or were not treated with pain medication for the control of post-operative pain and inflammation associated with soft-tissue surgical procedures such as abdominal surgery (e.g. ovariohysterectomy, abdominal cryptorchidectomy, splenectomy, cystotomy) or major external surgeries (e.g. mastectomy, skin tumor removal ≥ 8 cm).

In this field study, requirement for additional pain control following the various types of soft-tissue surgery was the primary efficacy parameter being evaluated. Only 8 (6.4%) of the Previcox® treated dogs needed additional pain control, whereas 31 (24.0%) of the unmedicated controls did, which constitutes a significant difference between the two groups.

Post-operative pain and inflammation associated with orthopedic surgery: Previcox® Chewable Tablets were evaluated in a negative-controlled, double-blinded, multi-center field study conducted in the United States, France, Germany, Italy and Switzerland, and involving client-owned animals to determine effectiveness of Previcox® in the control of pain associated with the surgical repair of a ruptured anterior cruciate ligament when used in combination with a morphine containing pre-anesthetic medication.

Out of 226 client owned dogs of various breeds enrolled in the study that underwent surgical procedures such as fabellar suture and/or imbrication, fibular head transposition, tibial plateau leveling osteotomy (TPLO) and “over the top” technique, 220 dogs were evaluated for effectiveness. Dogs ranged in age from 8 months to 17 years and weighed between 3.4 to 79.8 kg.

Dogs were randomly allocated to receive Previcox at a dose of 5 mg/kg body weight orally once on Day 0 (approximately 2 hours prior to their surgical procedure) and then orally once daily through Day 2, or sham dosing.

In this field study, requirement for additional pain control following the various types of orthopedic surgery was the primary efficacy parameter being evaluated. Only 13 (11.2%) of the Previcox® treated dogs needed additional pain control, whereas 39 (37.5%) of the unmedicated controls did, which constitutes a significant difference between the two groups.

Palatability: Previcox® Chewable Tablets were rated convenient to administer by approximately 95% of owners and palatable to the dog by approximately 65% of owners in worldwide multi-center field trials for osteoarthritis involving client-owned dogs of various breeds and sizes.

Animal Safety: In both laboratory studies and clinical field trials, Previcox® was well tolerated in dogs.

In a target animal safety study, firocoxib was administered orally to healthy adult Beagle dogs (eight dogs per group) at 5, 15, and 25 mg/kg (1, 3, and 5 times the recommended total daily dose) for 180 days. At the indicated dose of 5 mg/kg, there were no treatment related adverse events. Decreased appetite, vomiting, and diarrhea were seen in dogs in all dose groups, including unmedicated controls, although vomiting and diarrhea were seen more often in dogs in the 5X dose group. One dog in the 3X dose group was diagnosed with juvenile polyarteritis of unknown etiology after exhibiting recurrent episodes of vomiting and diarrhea, lethargy, pain, anorexia, ataxia, proprioceptive deficits, decreased albumin levels, decreased and then elevated platelet counts, increased bleeding times, and elevated liver enzymes. On histopathologic examination, a mild ileal ulcer was found in one 5X dog. This dog also had a decreased serum albumin which returned to normal by study completion. One control and three 5X dogs had focal areas of inflammation in the pylorus or small intestine. Vacuolization without inflammatory cell infiltrates was noted in the thalamic region of the brain in three control, one 3X, and three 5X dogs. Mean ALP was within the normal range for all groups but was greater in the 3X and 5X dose groups than in the control group. Transient decreases in serum albumin were seen in multiple animals in the 3X and 5X dose groups, and in one control animal.

In a separate safety study, firocoxib was administered orally to healthy juvenile (10-13 weeks of age) dogs at 6.9 (4.3-9.6) and 20.3 (12.8-29.0) for 180 days, and 33.5 (21.9-54.0) mg/kg for 84 days. There were six dogs per group except in the high dose group where twelve dogs were included. In the low dose group, on histopathologic examination, three out of six dogs had minimal periportal hepatic fatty change. On histopathologic examination, one control, one low dose, and two high dose dogs had diffuse slight hepatic fatty change. These animals showed no clinical signs and had no liver enzyme elevations. In the middle dose group, one dog in a moribund state was euthanized (Day 63). This dog also had a mildly decreased serum albumin. At study completion, out of five surviving and clinically normal middle dose dogs, three had minimal periportal hepatic fatty change. Of twelve dogs in the high dose group, one died (Day 82) and three moribund dogs were euthanized (Days 38, 78, and 79) because of anorexia, poor weight gain, depression, and in one dog, vomiting. One of the euthanized dogs had ingested a rope toy. Two of these high dose dogs had mildly elevated liver enzymes. At necropsy all five of the dogs that died or were euthanized had moderate periportal or severe panzonal hepatic fatty change; two had duodenal ulceration; and two had pancreatic edema. Of two other clinically normal high dose dogs (out of four euthanized as comparators to the clinically affected dogs), one had slight and one had moderate periportal hepatic fatty change. Drug treatment was discontinued for four dogs in the high dose group. These dogs survived the remaining 14 weeks of the study with no adverse findings at the study end. On average, the dogs in the middle and high dose groups did not gain as much weight as control dogs. Thalamic vacuolation was seen in three of six dogs in the middle dose group, five of twelve dogs in the high dose group, and to a lesser degree in two unmedicated controls. Diarrhea was seen in all dose groups, including unmedicated controls.

In another laboratory study, firocoxib was administered once daily to 4 young dogs aged 11-14 months at a dose of 50 mg/kg (10X) for 22 days; there were also 2 control dogs. At 10X, three of four dogs had decreased food consumption, vomiting, weight loss and intestinal erosion or ulceration of the duodenum or jejunum. Two of four dogs had decreased glucose, albumin, total protein and increased globulin. One dog also had increased BUN, creatinine, ALT, AST and hepatic lipidosis.

Storage: Previcox® should be stored at controlled room temperature (15°-30° C) with excursions up to 40° C permitted as long as they do not exceed 24 hours.

How Supplied: Previcox® is available as round, beige-tan, half-scored flavored chewable tablets in two strengths, containing 57 mg or 227 mg of firocoxib. One of the sides of each tablet is engraved with the following: “M” above the score; “57” below the score of the 57 mg tablets; “227” below the score of the 227 mg tablets. Each tablet strength is supplied in 10 or 30 count blister packages and 60 count bottles.

Merial Limited, a company limited by shares registered in England and Wales (registered number 3332751) with a registered office at PO Box 327, Sandringham House, Sandringham Avenue, Harlow Business Park, Harlow, Essex CM19 5QA, England, and domesticated in Delaware, USA as Merial LLC, and having its place of business at 3239 Satellite Boulevard, Duluth, GA, U.S.A.

037 834073

NAC No.: 11821314

MERIAL CANADA INC.20000 CLARK GRAHAM, BAIE D'URFÉ, QC, H9X 4B6

Telephone:

514-457-1555

Order Desk:

888-637-4251 (888-MERIAL1)

Fax:

514-457-1175

Website:

www.merial.ca

Email:

service.canada@merial.com

Every effort has been made to ensure the accuracy of the Previcox Chewable Tablets (227 mg) information published above. However, it remains the responsibility of the readers to familiarize themselves with the product information contained on the Canadian product label or package insert.

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